Translational Study of Nivolumab in Combination With Bevacizumab for Recurrent Glioblastoma

  • STATUS
    Recruiting
  • days left to enroll
    30
  • participants needed
    40
  • sponsor
    Ulrik Lassen
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Updated on 25 January 2021
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platelet count
corticosteroids
measurable disease
bevacizumab
recurrent disease
glioblastoma multiforme
temozolomide
recurrent glioblastoma

Summary

The aim of this study is to make preliminary assessment of PD-L1 and other immune related biomarkers that might act as predictors of anti-tumor activity of Nivolumab in patients with recurrent glioblastoma

Description

The effect of Nivolumab in oncologic diseases is to modulate the immune system in order to generate and/or restore a durable anti-tumor response leading to clearance of tumor. Clinical data generated with Nivolumab monotherapy in a variety of settings support the hypothesis that blockade of the PD-1 pathway results in rejection of tumor by the host immune system. The precise mechanisms by which Nivolumab exerts its anti-tumor activity are still under investigation. To contribute to this knowledge, tumor tissue from primary operation for all patients and tumor tissue from patients in the surgical Arm A will be used for further analysis.

Targeted sequencing with next generation sequencing (NGS) and Genome-wide Associations Studies (GWAS) with the use of single nucleotide polymorphism (SNP)-arrays and micro-array for expression profiling will be performed in order to describe the profile of the tumor. At Rigshospitalet has initiated a program of NGS of patients with GBM after informed content, by obtaining fresh tissue from primary or relapse surgery. In the surgical group (Arm A) of this study NGS will be repeated after one dose of Nivolumab. This information will be used in combination with the clinical observations for each patient receiving the combination of Nivolumab and Bevacizumab and the aim is that these results could be useful towards finding prognostic and/or predictive biomarkers in GBM.

In order to study the interaction between tumor cells and the immune system investigation of intratumoral and peripheral changes in tumor-infiltration lymphocytes (TILs) will be performed. By looking at TILs and peripheral blood lymphocytes (PBLs) Surgical samples will be compared to sequencing of baseline surgical samples (before Nivolumab). The interaction of TILs and tumor cells will be assessed with in vitro functional assays of autologous tumor cell recognition. Functional patterns of antitumor CD8+ and CD4+ TILs and PBLs will be investigated, with assays combining characterization of major T cell functions and simultaneous surface staining of PD-1 after co-culture with autologous tumor cells. This may detect treatment-induced changes in the functional repertoires of CD4+ and CD8+ TILs both in the tumor microenvironment (TILs) and in the periphery (PBLs). It is expected that these analyses will reveal whether significant functional changes (defined as increased frequency of tumor-reactive T cells or as functional shifting from a monofunctional to a multifunctional profile) are induced in the whole repertoire of T cells, or whether these changes are restricted to PD-1 positive T cells.

Regarding the immune-reactivity, CD8 T cell recognition of tumor-specific-antigens (TSA), i.e. and mutation derived neoepitopes will be analyzed in enrolled patients. To analyze for immune reactivity on a personalized basis by comprising epitope-maps based on both mutation-derived neoepitopes and shared tumor antigens selected based on the individual tumor mRNA expression level.

For the prediction of mutation- and splice-variation derived epitopes, whole exome sequencing (WES) and mRNA sequencing will be conducted on tumor versus germline-control samples. Cancer-specific mutations, indels, frameshifts and splice variations will be mapped to predict T cell epitopes overlapping these regions based on the patient HLA type, using available prediction tools, netMHC. A pipeline for processing next-generation sequencing data into tumor-specific neo-epitope maps has been generated to include analyses of tumor heterogeneity and generate personalized peptide libraries for each patient and analyze for T cell recognition of personalized neoepitopes in each patient included in the study. A novel technology will tag and track multiple (>1000) antigen specific T cell specificities based on their peptide-MHC (pMHC) recognition motif through a pMHC multimer with a co-attached 'DNA barcode'. Through use of this technology T cell recognition will be assessed against large libraries of peptides in limited biological samples, such as tissue biopsies, TILs and peripheral blood mononuclear cells (PBMCs). Data will reveal to what extend mutation and splice-variant derived neoepitopes are contributing to immune recognition as a consequence of checkpoint inhibition. If these are significantly recognized, then they are likely to play a crucial role for the clinical response to checkpoint inhibition.

Details
Condition Recurrent Adult Brain Tumor
Treatment bevacizumab, Nivolumab
Clinical Study IdentifierNCT03890952
SponsorUlrik Lassen
Last Modified on25 January 2021

Eligibility

 Yes No Not Sure

Inclusion Criteria

Pathologically confirmed GBM (including all histologic variants)
Age 18 years
Evidence of radiological (MRI-scan) measurable recurrent progressive GBM evaluated by the Response Assessment in Neuro-Oncology (RANO) criteria
In arm B measurable disease according to the RANO guidelines, within 14 days of starting treatment. Measurable disease after surgery on arm A is not required with radiographic evidence of recurrent disease after treatment with temozolomide and radiotherapy
An interval of at least 4 weeks between prior radiotherapy or chemotherapy and enrolment on this protocol
Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) 0-2
Life expectancy, in the opinion of the investigator > 3 month
Written informed consent obtained prior to any screening procedures. Patients must be willing and able to comply with the protocol and aware of the investigational nature of this study
Patients must have adequate bone marrow function and organ function within 2 weeks of study treatment as defined by the following laboratory criteria
Hematopoietic function: total white blood cell count (WBC) 3000/mm, absolute neutrophil count (ANC) 1500/mm, platelet count 125,000/mm; hemoglobin 9g/dL
Hepatic function: bilirubin < 1.5 times the upper limit of normal (ULN) (excluding Gilberts Syndrome, for which bilirubin must be < 4 times ULN), ALAT < 2.5 times ULN
Renal function: serum creatinine < 1.5 ULN or estimated creatinine clearance of 50 mL/min, calculated using the formula of Cockcroft and Gault
APTT and INR < normal limit
All female patients and partners of childbearing potential must agree to use adequate birth control during study treatment and for 5 months after the last dose of study drug and have a negative serum pregnancy test at screening. Acceptable methods of contraception are oral, implantable or injectable contraceptives, contraceptive patch, intrauterine device, or a sexual partner who is surgically sterilized or post-menopausal
Fertile males must be willing to employ adequate means of contraception during study treatment and for 7 months after the last dose of study drug
Archived paraffin-embedded tissue (approximately 10 unstained slides or a tumor block) must be available for confirmation of tumor diagnosis and correlative studies
Patients in the surgical arm (Arm A) must be predicted pre-operatively to have sufficiently sized recurrent tumor to allow for 500 mg of enhancing tumor and 300 mg of non-enhancing tumor to be resected
Patients must be on a stable or decreasing dose of corticosteroids (or none) for at least 5 days prior to MRI and maximum of a dose of 20 mg prednisolone per day at enrollment of the study

Exclusion Criteria

Patients must not have significant medical illness that in the investigator's opinion cannot be adequately controlled with appropriate therapy or would compromise the patient's ability to tolerate this therapy
Co-medication that may interfere with study results; e.g. immuno-suppressive agents other than corticosteroids (equivalent to max dose of 20 mg prednisolone per day) and stable for at least 5 days prior to day 1
Any condition (medical, social, psychological), which would prevent adequate information and follow-up
Any other active malignancy or previous malignancies within the last 5 years, except, adequately treated basal or squamous cell carcinoma of the skin, or carcinoma in situ
Uncontrolled hypertension (systolic blood pressure (BP) > 150 mmHg and/or diastolic BP > 100 mmHg), unstable angina, congestive heart failure (CHF) of any New York Heart Association (NYHA) classification, serious cardiac arrhythmia requiring treatment (exceptions: atrial fibrillation, paroxysmal supraventricular tachycardia), history of myocardial infarction within 6 months of enrollment
Clinically significant peripheral vascular disease
Evidence of bleeding diathesis, coagulopathy or taking ASA, NSAIDs or clopidogrel
Patients with coagulation problems and medically significant bleeding in the month prior to start of treatment (e.g., peptic ulcer, epistaxis, spontaneous bleeding)
Major surgical procedure, open biopsy, or significant traumatic injury within 28 days prior to day 0, anticipation of need for major surgical procedure during the curse of the study
Minor surgical procedures, fine needle aspirations or core biopsies within 7 days prior to day 0
History of abdominal fistula, gastrointestinal perforation or intra-abdominal abscess within 6 months prior to day 0
Known active hepatitis A, B or C infection; or known to be positive for HCV RNA or HBsAg (HBV surface antigen); hepatitis testing is not required
Known HIV infection; HIV testing is not required
Active infection requiring parenteral systemic antibiotics
Administration of a live, attenuated vaccine within 4 weeks before first dose of Nivolumab prior to surgery in Arm A or Cycle 1 Day 1 (Arm A and B) or anticipation that such a live attenuated vaccine will be required during the study. Influenza vaccination should be given during influenza season only (approximately October to March). Patients must not receive live, attenuated influenza vaccine (e.g., FluMist) within 4 weeks before first dose of Nivolumab prior to surgery in Arm A or Cycle 1 Day 1 (Arm A and B) or at any time during the study
Severe infections within 4 weeks prior to Cycle 1 Day 1, including but not limited to hospitalization for complications of infection, bacteremia, or severe pneumonia
Received oral or intravenous (IV) antibiotics within 2 weeks prior to Cycle 1 Day 1. Patients receiving prophylactic antibiotics (e.g., for prevention of a urinary tract infection or chronic obstructive pulmonary disease) are eligible
Any other diseases, metabolic dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that would contraindicate the use of an investigational drug
Dementia or altered mental status that would prohibit informed consent
History of organ allograft
History or risk of autoimmune disease, including but not limited to systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, vascular thrombosis associated with antiphospholipid syndrome, Wegners granulomatosis, Sjogrens syndrome, Bells palsy, Guillain-Barre syndrome, multiple sclerosis, vasculitis, or glomerulonephritis
History of idiopathic pulmonary fibrosis, pneumonitis (including drug induced), organizing pneumonia (i.e., bronchiolitis obliterans, cryptogenic organizing pneumonia, etc.), or evidence of active pneumonitis on screening chest CT scan. History of radiation pneumonitis in the radiation field (fibrosis) is permitted
Pregnant or breast-feeding women
Prior treatment with PD-1/PD-L1 inhibitors
Known hypersensitivity to any of the components of Nivolumab or Bevacizumab
Investigational therapy (defined as treatment for which there is no regulatory authority; within 28 days prior to Cycle 1 Day 1
Any approved anti-cancer therapy, including chemotherapy or hormonal therapy, within 3 weeks prior to Cycle 1 Day 1, with the following exceptions
Hormone-replacement therapy or oral contraceptives
Treatment with systemic immunosuppressive medications including, but not limited to: cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-TNF agents within 2 weeks prior to Cycle 1, Day 1. The use of inhaled corticosteroids and mineralocorticoids (e.g. fludrocortisone) for patients with orthostatic hypotension or adrenocortical insufficiency is allowed
Concurrent therapy with approved or investigational anticancer therapeutics
Body weight significantly below ideal body weight in the opinion of the investigator
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